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Keep At It: Improving an Old Strategy to Find New Treatments for Itch

Evidence from animals and human nerve cells points to a protein in the spinal cord as a potential treatment target for itch. Image credit: Tharakorn Arunothai/123RF Stock Photo.

Everyone knows how unpleasant itch can be, and the relief that comes from scratching. While short-term itch is commonly associated with skin irritation, researchers know less about the causes of chronic itch, a condition for which currently available treatments often don’t work.

Now, a recent study improves upon a previous strategy to treat itch, focusing on a protein known for its involvement in itch conditions.

Researchers at the U.S. National Institutes of Health (NIH) set their sights on natriuretic peptide receptor 1 (NPR1). This protein is found on nerve cells in the spinal cord that detect itch. While a previous attempt to quiet the activity of NPR1 with a drug was unsuccessful in treating itch, the new study identified a different drug that inhibited NPR1 and, in turn, eased itch in mice.

Additional experiments with human neurons showed that calming the activity of NPR1 may have similar beneficial effects in people with itch.

The study was published July 10, 2019, in the journal Science Translational Medicine. It was led by Hans Jürgen Solinski of the NIH’s National Institute of Dental and Craniofacial Research, in collaboration with James Inglese and colleagues at the NIH’s National Center for Advancing Translational Sciences.

Explaining a past setback–and finding a way to get over it
Previous work had pinpointed NPR1 as a potential drug target for the treatment of itch—that is, as a molecule that a drug could affect in a favorable way to provide itch relief.

In the current study, the researchers tried to identify new molecules that could change the activity of NPR1. They had to find something new because a past study found that a molecule called A-71915, which attaches to NPR1, was unable to prevent itch in mice.

But in the new study, the researchers found that A-71915 was not what it seemed. It turned out that this molecule had the ability to both quiet and activate NPR1. This was a possible explanation for why it had no effect on itch.

What the investigators needed was something “pure”—something that quieted, and only quieted, the activity of NPR1.

So the researchers set out to identify promising candidates for this job, looking to a large chemical database held at the National Center for Advancing Translational Sciences. They used an automated process to rank the chemicals based on their shape and how well they could inhibit NPR1.

This initial screen identified over 1,400 compounds for further study. The researchers then used a series of overlapping strategies to narrow down to three compounds that blocked the human version of NPR1, one of which was called JS-11.

Putting a new candidate to the test
The researchers then tested whether JS-11 could prevent itch in mice. To do so, they used a model of itch in which they injected histamine (an immune system chemical that is involved in inflammation and that causes itch) into the abdomen. This makes the mice scratch the affected area.

Mice that received JS-11 scratched much less in response to histamine—less than half as much, in fact. JS-11 also decreased scratching in response to a second substance known to cause itch in mice.

JS-11 did not have an impact on blood pressure or heart rate, at least not after a single dose. Examining these possible side effects is important since NPR1 is present in a variety of other tissues, such as the kidney. But, more studies are needed to see what happens after repeat doses.

What about treating itch in people? The general approach of focusing on NPR1 seems feasible, based on additional experiments the researchers performed using human nerve cells.

But JS-11 itself is not the best candidate, in part because it doesn’t attach to NPR1 as strongly as one would like. In the meantime, testing in larger animals is also needed before moving to human studies.

“There is a long and slow process involved in moving things forward,” said Mark Hoon, one of the study authors. “Testing in non-human primates is the gold standard for drug development, and I know that there are European labs that have used pigs as models. But we have to go through quite a lot of steps before we get there.”

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